Devices and methods to convert conventional imagers into lock-in cameras

ABSTRACT

Disclosed herein are devices and methods for modifying a conventional imager to have functional features similar to that of a lock-in camera. Optical mask devices are configured to be coupled to conventional imager sensors and the configuration of the mask devices can be adjusted to acquire image data in rapid succession. One variation of an optical mask device comprises a substrate comprising a pattern of light-blocking and light-transmitting regions and an attachment structure for coupling the optical mask device to the imager. The substrate is configured to adjust the position of the light-blocking regions and light-transmitting regions relative to the light-sensing region of the imager based on a set of one or more predetermined substrate configurations. In some variations, the mask device and/or the imager sensor may be mechanically moved relative to each other based on the set of one or more predetermined substrate configurations.

RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 15/988,799, filed May 24, 2018, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Patent ApplicationNo. 62/640,416, filed Mar. 8, 2018. These applications are incorporatedherein by reference in their respective entireties.

BACKGROUND

Imaging modalities such as optical coherence tomography (OCT) andultrasound-modulated optical tomography (UOT) can be used to generateimages of a target region in highly-scattering media. For example, OCTand UOT can be used for non-invasive imaging of tissue regions below askin surface. However, because biological tissue is a highly-scatteringmedium, the signal-to-noise ratio is fairly poor and limits theresolution of images acquired using OCT or UOT. Changes in the opticalproperties of the target region that occur during the acquisition timewindow may result in image blur and/or information loss, for example dueto decorrelation of the speckle interference pattern which is to bemeasured in these techniques. For example, changes in tissue bloodperfusion and/or neural activity can occur rapidly, decorrelating orotherwise corrupting UOT or OCT measurements, or other interferencebased or holographic measurements, if the measurements occur on a slowertimescale than the tissue decorrelation.

An imager having a very rapid image data acquisition rate (e.g., framerate) compared to the decorrelation timescale can help improve thesignal quality for OCT or UOT or other interference based or holographicmeasurement techniques in rapidly decorrelating turbid media. Oneexample of an imager potentially having a sufficiently fast frame rateis a lock-in camera, which is able to acquire multiple measurements of alight field rapidly at each detector pixel in a temporally precisefashion synchronized with an external trigger or oscillation, storingthe multiple measurements in multiple electronic charge storage “bins”within each pixel. Phase shifting holography operations using lock-incameras can help improve the resolution and signal quality oflow-coherence interferometry or UOT imaging. However, lock-in camerasensors often lack features that are common in high-performanceconventional imager sensors. For example, lock-in camera sensorscurrently have a lower pixel count and electron well-depth as comparedto conventional imager sensors. Other optical arrangements that simulatethe rapid data acquisition rate of lock-in cameras in the context ofspatially resolved holographic wavefront measurements use two or moreimagers with precise pixel-level alignment and matched optical pathlengths. One example of such optical arrangement is an imager systemcomprising a plurality of separate imagers that are optically alignedwith each other, such that any given pixel(s) on the imagers have aknown one-to-one correspondence with each other (OLIC configuration).However, the use of multiple precisely aligned imagers can be cumbersomeand prone to alignment errors. Accordingly, improvements to imagers forhigh-speed, high pixel-count image data acquisition are desirable.

SUMMARY

Disclosed herein are optical mask devices and methods for modifying aconventional imager to have functional features similar to that of alock-in camera. For example, the devices and methods described hereinmay allow a single conventional imager to perform the same phaseshifting holography or beat frequency demodulation operations as a 2-binor 4-bin lock-in camera or an OLIC imager system having two imagers orfour imagers, respectively. In one variation, the device may be anoptical mask device configured to be coupled to a conventional imagercomprising a sensor with a detector pixel array. The optical mask devicemay comprise a substrate comprising a pattern of light-blocking regionsand light-transmitting regions that controls the transmission of lightonto particular light-sensing regions of the imager sensor (e.g., tocertain set(s) of detector pixels of the imager sensor). The pattern onthe substrate may be fixed such that the locations and/or the opticalproperties (e.g., transmission and/or reflectance of light, etc.) of thelight-blocking regions and the light-transmitting regions remainsunchanged during an image acquisition window (e.g., exposure time of asingle frame of the imager sensor). Alternatively or additionally, thepattern on the substrate may vary (e.g., be tuned or modified) duringthe image acquisition window such that light data is acquired bydifferent sets of detector pixels of the imager sensor at differenttimes in a manner controlled by the changing substrate pattern. In somevariations, the locations and/or the optical properties of thelight-blocking and light-transmitting regions relative to alight-sensing region of an imager vary for different mask patterns. Insome variations, the optical mask device may be movable relative to theimager sensor and/or the imager sensor may be movable relative to theoptical mask device, such that different sets of detector pixels areexposed for the collection of light data at different times in aprogrammable or controllable fashion. For example, in variations wherethe mask pattern is static (i.e., unchanging), the imager sensor may berapidly shifted in position by a predetermined number of pixels (e.g.,about 1, 2, 3, 4 or more pixels) during the image acquisition timewindow. This may “streak” the acquired image data corresponding to asingle image point across the predetermined number of pixels such thatthe light from a single image point is impinged upon multiple detectorpixels over time. For example, a single image point may impinge upondistinct detector pixels at different times during one or more imagerexposures or frames. The “streak” can be in a linear pattern (e.g.,across rows or columns of the detector pixel array) or in a gridpattern.

In OCT and UOT or other holography or interference-based imagingapplications, including low-coherence interferometry imagingapplications, changing the relative positions of light-blocking (and/orlight-transmitting) regions of a mask relative to the light-sensingregion of a conventional imager sensor may simulate the function of alock-in camera for the acquisition of interference patterns or specklepatterns or images. Adjusting the mask configuration (either by changingthe mask pattern or changing the relative position of the mask patternto the imager sensor) to a set of predetermined patterns orpredetermined positions in synchrony with phase changes in the referencelight signal (and/or ultrasound signal in the case of UOT) may simulatethe effect of acquiring speckle image data using a lock-in camera. Forexample, adjusting the mask configuration to two (or four) predeterminedpatterns or positions in synchrony with two (or four) phase changes inthe reference light signal may acquire speckle image data thatapproximates the speckle image data acquired by a 2-bin (or 4-bin)lock-in camera.

In some variations, the pattern of an optical mask device may beelectrically (e.g., digitally) controlled, and may comprise, forexample, a spatial light modulator (SLM), a digital micromirror device(DMD), electrically tunable retro-reflector array or absorber array,and/or other very high-speed patterned electronic shutter. Electricallyadjusting the mask pattern can be used instead of, or in addition to,relative motion between the optical mask and the imager. Patterns oflight-blocking and light-transmitting regions on an optical mask device,such as the dimensions and locations of pattern features, may beadjusted to match the pixel size and dimensions of conventional imagersensors such that speckle image data may be acquired in the manner of alock-in camera while retaining desirable features (e.g., highpixel-count, increased electron well depth, etc.) and commercialavailability (e.g., high-volume, low-cost components) of conventionalimager sensors.

One variation of an optical mask device may comprise a mask substratecomprising an array of optical structures with electrically-tunableoptical properties, where the optical properties of the array of opticalstructures may be adjustable to alter a pattern of light-blockingregions and light-transmitting regions on the mask substrate, and anattachment structure for coupling the mask substrate to an imager suchthat the mask substrate is disposed over a light-sensing region of theimager. The array of optical structures may be configured to alter thepattern of the light-blocking regions and the light-transmitting regionsaccording to a first predetermined substrate configuration and a secondpredetermined substrate configuration, where portions of thelight-sensing region of the imager are located under thelight-transmitting regions of the mask substrate in the firstpredetermined substrate configuration and are located under thelight-blocking regions of the mask substrate in the second predeterminedsubstrate configuration. The light-transmitting region in the firstpredetermined substrate configuration is a light-blocking region in thesecond predetermined substrate configuration. The optical structures maycomprise one or more of the structures selected from a list consistingof stepped quantum well heterostructures, liquid crystal-basedtransmission modulators, digital micromirrors, spatial light modulators,and MEMS-based reflectors. The pattern may comprise alternating rows ofthe light-blocking regions and the light-transmitting regions, and/ormay comprise alternating columns of the light-blocking regions and thelight-transmitting regions, and/or may comprise a checkerboardarrangement of the light-blocking regions and the light-transmittingregions. The device may further comprise an input port configured toreceive a mask substrate configuration signal, where the mask substratemay be configured to alter the pattern at time points indicated by amask configuration signal. In some variations, the mask substrateconfiguration signal may comprise a synchronization signal thatsynchronizes a light source light pulse with a mask substrateconfiguration change. A light signal of the light source may changephase at each light pulse and the light source may be a light source ofan interferometry system that produces an interference pattern in theform of a speckle image. The mask substrate may be configured totransition between the first predetermined substrate configuration tothe second predetermined substrate configuration at change of phase ofthe interference pattern. The light signal phase changes and substrateconfiguration changes may occur within a speckle decorrelation timeinterval. The array of optical structures may be configured to alter thepattern according to a third predetermined substrate configuration and afourth predetermined substrate configuration, where portions of thelight-sensing region of the imager located under the light-transmittingregions of the mask substrate in any one of the four predeterminedsubstrate configurations are located under the light-blocking regions ofthe mask substrate in any one of the other three predetermined substrateconfigurations. In some variations, the pattern may comprise one or moreof the light-transmitting regions having a total area that occupiesabout 50% of the total area of the mask substrate. In some variations,the pattern comprises one or more of the light-transmitting regionshaving a total area that occupies about 25% of the total area of themask substrate.

Also disclosed herein are methods for non-invasive optical detection ofneural activity. One variation of a method may comprise adjusting anoptical mask device disposed over a light-sensing region of an imager tohave a first pattern of light-blocking regions and light-transmittingregions, acquiring a first set of light interference pattern data frombrain matter at a first time point using a first set of detector pixelsin the light-sensing region of the imager, adjusting the optical maskdevice to have a second pattern of light-blocking regions andlight-transmitting regions, acquiring a second set of light interferencedata from brain matter at a second time point using a second set ofdetector pixels in the light-sensing region of the imager, andcalculating a first light intensity value by combining intensity valuesof each detector pixel in the first set of detector pixels andcalculating a second light intensity value by combining intensity valuesof each detector pixel in the second set of detector pixels. Thedetector pixels in the second set may be different from the detectorpixels in the first set. The first light interference pattern data maycomprise a combination of a first reference light signal having a firstphase and a first sample light signal from a target voxel in the brainmatter, and the second light interference pattern data may comprise acombination of a second reference light signal having a second phase anda second sample light signal from the target voxel. For example, thefirst phase may be 0 and the second phase may be π. In some variations,the method may further comprise adjusting the optical mask to have athird pattern of light-blocking regions and light-transmitting regions,acquiring a third set of light interference data from brain matter at athird time point using a third set of detector pixels in thelight-sensing region of the imager, where the third light interferencepattern data comprises a combination of a third reference light signalhaving a third phase and a third sample signal from the target voxel,adjusting the optical mask to have a fourth pattern of light-blockingregions and light-transmitting regions, acquiring a fourth set of lightinterference data from brain matter at a fourth time point using afourth set of detector pixels in the light-sensing region of the imager,where the fourth light interference pattern data comprises a combinationof a fourth reference light signal having a fourth phase and a fourthsample signal from the target voxel, and calculating a third lightintensity value by combining intensity values of each detector pixel inthe third set of detector pixels and calculating a fourth lightintensity value by combining intensity values of each detector pixel inthe fourth set of detector pixels. The first phase may be 0, the secondphase may be π/2, the third phase may be π, and the fourth phase may be3π/2. The method may further comprise determining a physiologicaloptical parameter of the target voxel based on the first, second, third,and fourth light intensity values.

Optionally, some methods may comprise determining a physiologicaloptical parameter of the target voxel based on the first and secondlight intensity values. The physiological optical parameter may be thelevel of deoxygenated and/or oxygenated hemoglobin concentration ofrelative abundance, and/or the physiological optical parameter is thelevel of neuronal movement or activity of brain matter. In somevariations, the first and second sample light signals may each befrequency encoded, and/or the first and second sample light signals maybe frequency encoded using ultrasound pulses delivered to the targetvoxel. Alternatively or additionally, the first and second sample lightsignals may each be path length encoded.

One variation of a method for non-invasive optical measurement of neuralactivity may comprise adjusting positions of light-blocking andlight-transmitting regions of an optical mask at a predetermined number(X) of time points to a plurality of predetermined positions thatcorrespond with a predetermined number (X) of phases of a sample lightsignal, wherein the optical mask is disposed over a detector pixel arrayof an imager, acquiring light interference data for each of theplurality of predetermined positions using the detector pixel array, andcalculating a plurality (X) of light intensity values corresponding tothe number (N) of phases of the sample light signal by averaging imagerdetector pixel values for each of the predetermined number (X) of timepoints, where changes in the plurality of light intensity values overtime represent neural activity.

One variation of an optical mask device may comprise a mask substratethat comprises an array of optical structures with electrically-tunableoptical properties and a pattern of light-blocking regions andlight-transmitting regions and an attachment structure for coupling theoptical mask to an imager such that the mask substrate is disposed overa light-sensing region of the imager. The optical properties of theoptical structures may be adjustable to alter the pattern of thelight-blocking and the light-transmitting regions and may be configuredto alter the pattern of the light-blocking regions andlight-transmitting regions according to a first predetermined substrateconfiguration and a second predetermined substrate configuration.Portions of the light-sensing region of the imager located underlight-transmitting regions of the mask substrate in the first substrateconfiguration may be located under light-blocking regions of the masksubstrate in the second substrate configuration. For example, alight-transmitting region in the first predetermined substrateconfiguration may be a light-blocking region in the second predeterminedsubstrate configuration. The optical structures may comprise one or moreof the structures selected from a list consisting of stepped quantumwell heterostructures, liquid crystal-based transmission modulators,digital micromirrors, spatial light modulators, and MEMS-basedreflectors. In some variations, the pattern may comprise alternatingrows of light-blocking regions and light-transmitting regions, or thepattern may comprise alternating columns of light-blocking regions andlight-transmitting regions, or the pattern may comprise a checkerboardarrangement of light-blocking regions and light-transmitting regions.Alternatively or additionally, the pattern may comprise one or morelight-transmitting regions having a total area that occupies about 50%of the total area of a substrate, or may comprise one or morelight-transmitting regions having a total area that occupies about 25%of the total area of a substrate. A mask device may further comprise aninput port configured to receive a mask substrate configuration signal,where the mask substrate may be configured to alter the pattern at timepoints indicated by the mask configuration signal. The mask substrateconfiguration signal may comprise a synchronization signal thatsynchronizes a light source pulse with a mask substrate configurationchange. A light signal of the light source may change phase at eachpulse and the light source may be a light source of an interferometrysystem that produces an interference pattern in the form of a speckleimage or pattern, and the substrate may be configured to transitionbetween the first predetermined substrate configuration to the secondpredetermined substrate configuration at each light signal phase change.Examples of interferometry systems that may comprise an imager and anyof the mask devices described herein may include, but are not limitedto, low-coherence interferometry systems, optical coherence tomographysystems (e.g., swept-source OCT), and ultrasound-modulated opticaltomography. In some variations, the light signal phase changes andsubstrate configuration changes may occur within a speckle decorrelationtime interval. The mask substrate may comprise a third predeterminedsubstrate configuration and a fourth predetermined substrateconfiguration, where portions of the light-sensing region of the imagerlocated under light-transmitting regions of the mask substrate in anyone of the four predetermined substrate configurations are located underlight-blocking regions of the mask substrate in any one of the otherthree predetermined substrate configurations.

Another variation of an optical mask device may comprise a masksubstrate comprising an actuator configured to move the light-sensingregion of the imager with respect to the substrate and a pattern oflight-blocking regions and light-transmitting regions, and an attachmentstructure for coupling the optical mask to an imager such that thesubstrate is disposed over a light-sensing region of the imager. Theactuator may be configured to move the mask substrate between a firstpredetermined substrate configuration and a second predeterminedsubstrate configuration, where the mask substrate is at a first locationwith respect to the light-sensing region of the imager when in the firstsubstrate configuration and the mask substrate is at a second locationwith respect to the light-sensing region of the imager when in thesecond substrate configuration. Portions of the light-sensing region ofthe imager located under light-transmitting regions of the substrate inthe first substrate configuration may be located under light-blockingregions of the substrate in the second substrate configuration.Optionally, the device may further comprise an actuator configured tomove the light-sensing region of the imager with respect to the masksubstrate. The actuator may be a piezo actuator, and may be configuredto move the substrate from about 2 μm to about 10 μm relative to thelight-sensing region of the imager. The device may also comprise asubstrate position sensor. In some variations, the pattern may comprisealternating rows of light-blocking regions and light-transmittingregions, or the pattern may comprise alternating columns oflight-blocking regions and light-transmitting regions, or the patternmay comprise a checkerboard arrangement of light-blocking regions andlight-transmitting regions. Alternatively or additionally, the patternmay comprise one or more light-transmitting regions having a total areathat occupies about 50% of the total area of a substrate, or maycomprise one or more light-transmitting regions having a total area thatoccupies about 25% of the total area of a substrate. A mask device mayfurther comprise an input port configured to receive a mask substrateconfiguration signal, where the mask substrate may be configured toalter the pattern at time points indicated by the mask configurationsignal. The mask substrate configuration signal may comprise asynchronization signal that synchronizes a light source pulse with amask substrate configuration change. A light signal of the light sourcemay change phase at each pulse and the light source may be a lightsource of a low-interferometry system that produces an interferencepattern in the form of a speckle image, and the substrate may beconfigured to transition between the first predetermined substrateconfiguration to the second predetermined substrate configuration ateach light signal phase change. In some variations, the light signalphase changes and substrate configuration changes may occur within aspeckle decorrelation time interval. The mask substrate may comprise athird predetermined substrate configuration and a fourth predeterminedsubstrate configuration, where portions of the light-sensing region ofthe imager located under light-transmitting regions of the masksubstrate in any one of the four predetermined substrate configurationsare located under light-blocking regions of the mask substrate in anyone of the other three predetermined substrate configurations.

Also disclosed herein are methods for non-invasive optical detection ofneural activity. One variation of a method for non-invasive opticaldetection of neural activity may comprise adjusting an optical maskdevice disposed over a light-sensing region of an imager to have a firstpattern of light-blocking regions and light-transmitting regions,acquiring a first set of light interference pattern data from brainmatter at a first time point using a first set of detector pixels in thelight-sensing region of the imager, adjusting the optical mask device tohave a second pattern of light-blocking regions and light-transmittingregions, acquiring a second set of light interference data from brainmatter at a second time point using a second set of detector pixels inthe light-sensing region of the imager, and calculating a first lightintensity value by averaging combining intensity values over the firstset of detector pixels and calculating a second light intensity value byaveraging combining intensity values over the second set of detectorpixels. The detector pixels in the second set may be different from thedetector pixels in the first set. The first light interference patternmay comprise a combination of a first reference light signal having afirst phase and a first sample light signal from a target voxel in thebrain matter and the second light interference pattern may comprise acombination of a second reference light signal having a second phase anda second sample signal from the target voxel. The first phase may be 0and the second phase may be π. The method may further comprisedetermining a physiological optical parameter of the target voxel basedon the first and second light intensity values. The physiologicaloptical parameter may be the level of deoxygenated and/or oxygenatedhemoglobin concentration of relative abundance, or the level of neuronalmovement or activity of brain matter. In some variations, the first andsecond sample light signals may each frequency encoded. For example, thefirst and second sample light signals may be frequency encoded usingultrasound pulses delivered to the target voxel. In some variations, thefirst and second sample light signals may each path length encoded. Themethod may further comprise adjusting the optical mask to have a thirdpattern of light-blocking regions and light-transmitting regions,acquiring a third set of light interference data from brain matter at athird time point using a third set of detector pixels in thelight-sensing region of the imager, where the third light interferencepattern may comprise a combination of a third reference light signalhaving a third phase and a third sample signal from the target voxel,adjusting the optical mask to have a fourth pattern of light-blockingregions and light-transmitting regions, acquiring a fourth set of lightinterference data from brain matter at a fourth time point using afourth set of detector pixels in the light-sensing region of the imager,where the fourth light interference pattern may comprise a combinationof a fourth reference light signal having a fourth phase and a fourthsample signal from the target voxel, and calculating a third lightintensity value by combining intensity values over the third set ofdetector pixels and calculating a fourth light intensity value bycombining intensity values over the fourth set of detector pixels. Thefirst phase may be 0, the second phase may be π/2, the third phase maybe π, and the fourth phase may be 3π/2, and in some variations, themethod may further comprise determining a physiological opticalparameter of the target voxel based on the first, second, third, andfourth light intensity values.

In one variation, a method for non-invasive optical measurement ofneural activity may comprise adjusting positions of light-blocking andlight-transmitting regions of an optical mask at a predetermined number(X) of time points to a plurality of predetermined positions thatcorrespond with a predetermined number (X) of phases of a sample lightsignal, where the optical mask is disposed over a detector pixel arrayof an imager, acquiring light interference data for each of theplurality of predetermined positions using the detector pixel array, andcalculating a plurality (X) of light intensity values corresponding tothe number (N) of phases of the sample light signal by averaging imagerdetector pixel values for each of the predetermined number (X) of timepoints, where changes in the plurality of light intensity values overtime represent neural activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic depiction of one variation of an imaging assemblycomprising an optical mask device. FIG. 1B is a conceptual depiction ofan image acquisition method using the imaging assembly of FIG. 1A.

FIG. 2A is a schematic depiction of one variation of an optical maskdevice. FIG. 2B depicts one variation of a mask substrate pattern. FIG.2C depicts another variation of a mask substrate pattern. FIG. 2Ddepicts a set of four predetermined mask substrate patterns orconfigurations. FIG. 2E depicts the mask substrate patterns of FIG. 2Ddisposed over an image sensor for detecting four interference patternsor speckle images. FIG. 2F is a schematic representation of a subset ofthe image sensor detector pixels that correspond with thelight-transmitting regions of the mask substrate patterns of FIG. 2D.FIGS. 2G and 2H are schematic depictions of different mask substratepatterns or configurations and corresponding mask configuration signals.

FIG. 3A is a schematic representation of one variation of an imagingsystem comprising an optical mask device. FIG. 3B is a schematicrepresentation of another variation of an imaging system comprising anoptical mask device.

FIG. 4A is a schematic representation of one variation of an imagingsystem comprising an two imager sensors. FIG. 4B is a timing diagramassociated with the use of the system of FIG. 4A.

FIG. 5A is a flowchart depiction of one variation of a method fornon-invasive optical detection of neural activity. FIG. 5B is aflowchart depiction of one variation of a method for non-invasiveoptical detection of neural activity.

DETAILED DESCRIPTION

Described herein are optical mask devices configured to be coupled toand disposed over conventional imager sensors and methods of adjustingthe configuration of the mask devices to acquire image data in rapidsuccession. Methods may comprise adjusting the configuration of a maskdevice and acquiring multiple sets of image data (e.g., of interferencepatterns or speckle images) in synchrony with an external trigger atpredetermined acquisition time points. The mask may have a particularmask configuration for each predetermined acquisition time point, andthe set of detector pixels that are located in the light-transmittingregions of the mask may acquire a set of detector pixel data at thatacquisition time point. The different sets of data acquired by differentset of detector pixels at the different acquisition time points may beanalogous to image data collected in multiple electronic charge storage“bins” of the detector pixels in a lock-in camera. By adjusting the maskconfiguration at each data acquisition time point, a conventional imagermay be configured to rapidly capture and store multiple sequentialsamples of image data, with sample-to-sample latencies shorter thanreadout times of conventional imagers. The devices and methods describedherein may be used, for example, to create a 2-bin, 4-bin or any othernumber of temporally separated bins of image data measurements for eachspeckle by impinging the light from the speckle on different imagerpixels or combinations of pixels at different times.

An imager may be any assembly or system comprising an imager sensor thatrecords light data that may be used to generate an image. An imagersensor may comprise an array of charged coupled device (CCD) orcomplementary metal-oxide semiconductor (CMOS) units or detector pixels.A conventional imager is one in which each detector pixel acquires andretains light data for a moment in time. Successive light measurementsby a detector pixel “overwrites” the previous light measurement in thatdetector pixel. Optionally, an imager may comprise one or more opticalcomponents disposed over the imager sensor. Optical components mayinclude one or more of a transparent window, a lens (e.g., objectivelens, relay lens, etc.), a filter (e.g., polarizing filter, wavelengthor color filter, mosaic filter, neutral density filter, etc.), a prism,a condenser, a shutter (e.g., a variable aperture component), and thelike. Examples of imagers may include, but are not limited to, line scancameras, CCD arrays, CMOS arrays, sCMOS arrays, EM-CCD arrays,photodiode arrays, avalanche diode arrays, extended well depth cameras,wrap-around cameras, CMOS smart pixel devices or other types of imagers.

An interferometry system (e.g., OCT, low-coherence interferometry, UOT)may comprise a light source and a beam splitter that directs a portionof the light beam (i.e., sample light) to the tissue sample of ananatomical structure (e.g., the anatomical structure is this case may bethe intact head of a patient, including the scalp, skull, and brain,with the tissue voxel comprising brain tissue), while directing anotherportion of the light beam along a variable (but known) light path (i.e.,reference light). The sample light interacts with the tissue sample, andthe sample light that interacts with a target tissue region such as atarget tissue voxel of brain matter (i.e., signal light) in combinationwith sample light that interacts with surrounding tissue regions (i.e.,background light) may produce a sample light pattern that is directed oremitted back away from the tissue sample. The sample light pattern maythen be combined with the reference light to create an interferencelight pattern (e.g., a speckle image) that selects sample photons thathave a path length that is the same as, or similar to, the path lengthof the reference light. A UOT system may comprise an interferometrysystem as described above as well as an acoustic assembly configured fordelivering ultrasound (e.g., focused ultrasound pulses) into the targettissue region or target voxel. The ultrasound pulse may shift thefrequency of the sample light at the target tissue region by theultrasound frequency (i.e., “tagging” the sample light). The focusedultrasound pulse may have little or no impact on the photons of thebackground light (i.e., “untagged” background light). The referencelight may also be frequency-shifted by the ultrasound frequency so thatcombining the reference light and the sample light pattern creates aninterference pattern that selects sample photons that have the samefrequency shift (i.e., selecting tagged photons). When low-coherenceinterferometry or UOT modalities are used for non-invasive imaging ofbrain matter below the skin surface and/or below the skull (or anytarget region in a highly-scattering medium), the reference light signalmay cycle through a plurality of preselected or predetermined phaseshifts to generate a plurality of interference or speckle patterns fromcombining sample light emerging from the brain matter (or scatteringmedium) and the phase-shifted reference light signal. The referencelight may step through these phase shifts rapidly, for example, fasterthan a speckle decorrelation time interval of about 1 ms or less, about100 μs or less, depending on the imaging depth in tissue, etc., whichmay be faster than the acquisition or frame rate of conventional imagersensors. The speckle decorrelation time is the time interval beyondwhich speckle data becomes uncorrelated. When the time interval betweensuccessive measurements is greater than or equal to the speckledecorrelation time, then the random phase offset and/or background willchange between the successive measurements, which may corrupt themeasurement such that the calculation of the intensity or amplitude ofthe quasi-ballistic photon fraction is no longer possible and/oraccurate. The speckle decorrelation time may vary depending on theoptical properties of the tissue and/or the selected imaging depthwithin the tissue, and may be, for example, less than 1 millisecond forimaging more than 3 mm deep into living brain tissue, and/or less than100 microseconds for imaging through the skull and into the corticalbrain tissue underneath). The speckle decorrelation time for aparticular interferometry system may be measured using a lock-in cameraand/or any of the mask devices described herein disposed over an imager.Lock-in cameras may be configured to measure these rapidly-changinginterference patterns or speckle images by measuring each speckle of thespeckle image at time points that correspond with the timing of each ofthe phase shifts and storing that data in a pixel data storage bin. Theimaging systems described herein may be configured to measure theinterference patterns at each phase shift time point by changing themask configuration to a pattern that corresponds to that time point, andmeasuring each speckle of the speckle image using one or more detectorpixels that correspond to that time point or phase shift. The speckleimage data is stored in a plurality of detector pixels that correspondwith that time point or phase shift, as opposed to being stored in aparticular data bin of a pixel of a lock-in camera.

In some variations, an imaging system comprising an optical mask deviceand a conventional imager sensor may be used to measure atime-varying/modulated intensity of the light in each speckle atdifferent time-points in the manner of heterodyne detection, e.g., inorder to selectively extract the AC component from a DC background.Individual different pixels and/or combinations of (e.g., neighboring)detector pixels on a conventional imager sensor may be used to sense andstore these distinct measurements. In contrast, a lock-in camera may usedifferent electronic data bins of the same photodetector pixel to storethese distinct measurements, and an OLIC system may use two or morepixel-by-pixel aligned imagers to achieve a similar effect by recordingmultiple interferences for the same speckle in a single snapshot on thecorresponding aligned pixels of the multiple imagers. Adjusting theoptical mask device in a time-varying manner may direct light from eachspeckle to the imager sensor detector pixel(s) corresponding to eachtime point cause, causing the detector pixel(s) of the imager sensor tostore different time points of the interference pattern at a givenspeckle. Adjusting the optical mask device may comprise changing thepattern of light-transmitting and light-blocking regions and/or changingthe position of the light-transmitting and light-blocking regions of themask by adjusting the alignment between the imager sensor and the maskover time (e.g., at each time point).

While the devices and methods described herein are explained in thecontext of low-coherence interferometry and UOT, it should be understoodthese devices and methods may be used in any imaging context where rapidacquisition of image data at precise or predetermined time points orintervals, and/or in synchrony with an external trigger signal isdesired (e.g., in any imaging context where a lock-in camera is used).The devices and methods described herein may be used to detect lightmodulated (e.g., via amplitude or phase modulation) by other mechanisms,for instance via an external modulator applied before light enters thesample. For example, the devices and methods described herein may beused to measure phase shifts in the modulation of light, which may beused to calculate average time-of-flight variations from a light sourceto a detector located on the surface of the brain. This can be used tomeasure fast changes in the optical scattering properties of the brainmatter between light source and detector, which may be indicative offast changes in neural activity (similar to the use of frequency domaindiffuse optical tomography). The device and methods described herein maybe used for measuring changes in speckle patterns as a function of time,independent of locking to a particular modulation frequency. Examplesmay include measuring phase-shifted holograms, and/or measuringmodulations or oscillations at a particular beat frequency, and/ormeasuring changes in a speckle pattern (e.g., to calculate the speckledecorrelation interval) that occur faster than the frame rate of aconventional imager. These measurements may be made with or without areference light signal, light signal phase shifts, ultrasonicmodulation, or optoacoustic modulation. In addition, this approach maybe used to detect externally modulated light for the purpose ofmultiplexing light signals from many sources, which each light signalmay be modulated differently.

FIG. 1A is a schematic depiction of an imaging system (100) comprisingan imager (101) having an imager sensor (106) and an optical mask device(102) disposed over the imager sensor and FIG. 1B depicts examples ofspeckle image data acquired by the system of FIG. 1A. The imaging system(100) may comprise an optical mask device (102) comprising a masksubstrate (104), and an imager comprising an imager sensor (106)comprising an array of detector pixels. In this variation, the imagersensor (106) may be coupled to one or more actuators (108) that areconfigured to position the imager sensor (106) relative to the opticalmask device (102) along the arrow (103) and the optical mask device(102) may be stationary. Alternatively or additionally, the optical maskdevice (102) may be coupled to one or more actuators that are configuredto move the mask device relative to the imager sensor (106). The leftside of FIG. 1A represents two interference patterns (110 a, 110 b) orspeckle images that may be measured by a single frame of the imagersensor (106). The pattern on the mask substrate (104) may comprise aseries of light-transmitting stripes alternating with a series oflight-blocking stripes, which may be vertical as depicted in FIG. 1B ormay be horizontal, though other orientations (e.g., stripes at any anglebetween 0° and 90°, stripes at about 30°, stripes at about 45°, etc.)may be possible. The two different speckle images (e.g., produced byinterferometry at different reference beam phase shifts, or otherwise)may be captured on alternating columns of the imager sensor (106). Thefirst and second speckle patterns may be mapped to alternating odd andeven columns of the imager sensor by moving the optical mask (102)relative to the imager sensor (106) and/or moving the sensor (106)relative to the optical mask (102) and/or changing the pattern on themask substrate (104) such that the stripes of light-blocking andlight-transmitting regions are flipped. A mask configuration describesthe relative locations of the light-transmitting region(s) and thelight-blocking region(s) of a mask substrate relative to an imagersensor, including, but not limited to, the location of the optical maskdevice and/or mask substrate relative to the imager sensor, and/orchanges in the optical characteristics of mask substrate regions suchthat the arrangement or pattern of light-transmitting and light-blockingregions changes on the mask substrate. The optical mask device (102) maybe adjusted to the first mask configuration (112) to detect the firstspeckle image (110 a) and the optical mask may be adjusted to the secondmask configuration (114) to detect the second speckle image (110 b). Theoverall image detected by the imager sensor (106) is represented by thecomposite image (116), where the detector pixel data in the odd columnspertain to the first speckle pattern and the detector pixel data in theeven columns pertain to the second speckle pattern. As depicted in thecomposite image (116), each speckle image may undergo a signal loss ofabout 50% due to the mask pattern where about half the pattern compriseslight-blocking regions. In the context of non-invasive brain imaging,the variation in interference or speckle patterns may be due tophysiological changes in the brain, such fast changes in opticalscattering properties in the brain induced by ultrasound or othermodulation, and/or holographic phase shifting of a reference beam, forexample. The mask configuration may change from the first configurationto the second configuration within a speckle decorrelation time interval(e.g., about 1 ms or less, 100 μs or less).

In the case of UOT, the difference between the two speckle orinterference patterns may be an indicator of the amount ofultrasonically tagged light. In the case of low-coherenceinterferometry, the difference between the two speckle patterns mayrepresent the differentiation of short-path and long-path wavefronts byisolating interference terms due to path-length-selected photons. Thenumber of speckle patterns measured during an acquisition time window(e.g., less than or equal to the acquisition time for a frame of data ofthe imager sensor, less than a speckle decorrelation time interval, fromabout 5 μs to about 100 μs, about 10 μs, about 20 μs, about 40 μs, about50 μs, about 100 μs, from about 500 μs to about 1 ms, about 800 μs,about 1 ms, etc.) may be determined at least in part by the number ofmask configuration changes in the acquisition time window and thepattern of light-transmitting and light-blocking regions for each ofthose mask configurations. For example, to measure 10 speckle images at10 acquisition time points within an acquisition time window, theoptical mask may have 10 mask patterns where the light-transmittingregion in each pattern makes up about a tenth of the area of thesubstrate. For example, if the mask substrate were divided into columnsor vertical stripes, every tenth column or stripe would correspond to aparticular interference or speckle pattern. The mask may step througheach of the 10 patterns or configurations during the acquisition window(i.e., one pattern per time point), resulting in a composite image wherea tenth of the detector pixel data pertains to one interference orspeckle pattern.

Devices and Systems

FIG. 2A depicts one variation of an optical mask device (200) comprisinga mask substrate (202) having a substrate pattern comprising anarrangement of light-blocking and light-transmitting regions on the masksubstrate (which may also be referred to as a substrate) and one or moreattachment structures (204) configured to couple the mask device (200)to an imager. The substrate (202) may comprise an array of opticalstructures (203). In some variations, the optical properties of theoptical structures (203) may be electrically-tunable to form a desiredsubstrate pattern of light-blocking and light-transmitting regions.Alternatively, the optical properties of the optical structures (203)may be fixed in a specific pattern of light-blocking regions andlight-transmitting regions. An attachment structure may comprise a framestructure or support structure (205) comprising a central opening (207).The mask substrate (202) may be attached to the support structure (205),for example, by coupling the outer perimeter of the mask substrate (202)to the portions of the support structure (205) around the perimeter ofthe central opening, such that the substrate pattern (203) is locatedwithin the central opening (207). The mask substrate (202) may beconfigured to alter the pattern of the light-blocking andlight-transmitting regions according to one or more predetermined masksubstrate configurations. A mask substrate configuration may comprise aparticular substrate pattern and/or a particular position of thesubstrate (or optical mask device) and/or particular positions of thelight-transmitting regions and/or light-blocking regions relative to theimager sensor (i.e., light-sensing region of the imager). The patternsof light-transmitting and light-blocking regions of differentpredetermined substrate configurations may be selected such that alight-transmitting region in one configuration is a light-blockingregion in the other configurations. Alternatively or additionally, theposition or location of the mask substrate relative to the light-sensingregion of the imager to which the optical mask device is attached may bevaried according to the predetermined substrate configurations. Moregenerally, the substrate patterns or positions of the light-transmittingregions and the light-blocking regions of the mask substrate relative tothe light-sensing region of the imager may be such that portions of thelight-sensing region of the imager located under the light-transmittingregions of the mask substrate in one predetermined mask substrateconfiguration are located under the light-blocking regions of the masksubstrate in the other mask substrate configurations. That is, everydetector pixel of an imager sensor is exposed to incident light in onemask substrate configuration or substrate pattern, and is blocked fromincident light the remaining mask substrate configurations or substratepatterns. In some variations, the optical mask device (200) may compriseelectrical circuitry (206) comprising interface electronics configuredto send and receive signals from the imager and/or imaging systemcontroller (examples of which are described below and depicted in FIGS.3A-3B). The electrical circuitry (206) may comprise, for example, aninput port (209) that receives mask substrate configuration data orcommands, synchronization or trigger signals that regulate the timing ofmask substrate configuration changes, and the like. In some variations,the mask substrate (202) may comprise one more actuators (e.g., piezoactuators) configured to move the mask device relative to the imager towhich the mask device is attached. The one or more actuators may be incommunication with the electrical circuitry (206) so that motioncommands from the imaging system controller may be used to control theoperation of the one or more actuators. Optionally, the optical maskdevice (200) may comprise a position sensor (208) in communication withthe electrical circuitry (206), and mask substrate position data may betransmitted to the imaging system controller. The system controller mayadjust the operation of the one or more actuators based on the data fromthe position sensor (208) (e.g., position sensor data may be used as afeedback signal to confirm that the one or more actuators arefunctioning properly). Any of the optical mask devices described hereinmay be manufactured, and/or packaged, and/or sold as an individualcomponent, separate from any imaging system or assembly. Alternativelyor additionally, and of the optical mask devices described herein may bemanufactured, and/or packaged, and/or sold in conjunction with an imagersensor. The optical mask devices described herein may be used with anexisting interferometry system (e.g., low-coherence interferometrysystem, OCT, UOT) and/or any imaging system.

In some variations, attachment structures may comprise snap-fitmechanisms, screw-fit mechanisms, adhesive mechanisms, and the like. Insome variations, the mask substrate may be attached directly to theimager sensor to from an imager assembly, which may be enclosed in asingle housing. An imager assembly comprising an optical mask device andan imager sensor may be included in any imaging system, such as aninterferometry system for non-invasive brain imaging. In somevariations, the mask substrate may not physically touch the imagersensor but may be aligned with the imager sensor through a mechanicalcoupling structure, such as any of the attachment structures describedabove, that allows for independent alignment and or calibration. Theoptical mask device may be attached to the imager sensor during themanufacturing process of an imager assembly. Alternatively oradditionally, the optical mask device may be attached to an existingimager sensor (e.g., as an after-market modification).

A mask substrate may comprise one or more patterns of light-blockingregions and light-transmitting regions. In some variations, the masksubstrate may have a predetermined set of patterns, where the number ofpatterns may correspond to the number of data acquisition time points inan acquisition time window or frame. In the context of low-coherenceinterferometry or UOT, the number of predetermined mask patterns orconfigurations may correspond with the number of predetermined phaseshifts of a reference light signal. In some variations, a mask substratemay have a single pattern that remains constant or static during speckleimage acquisition. Light-blocking regions may be regions of the masksubstrate that completely obstructs or greatly attenuates thetransmission of light, so that detector pixels located underlight-blocking regions of a mask receive few (if any) photons of aspeckle image (for instance). For example, light-blocking regions maycomprise structures or materials that optically absorb or reflect all(or nearly all) incoming light so that little (if any) light is incidenton the detector pixels under those regions. Light-transmitting regionsmay be regions of the mask substrate that allow for the unimpededtransmission of light, so that detector pixels located underlight-transmitting regions of the mask receive the photons of a speckleimage (for instance). For example, light-transmitting regions maycomprise structures or materials that are optically transparent suchthat incoming light is transmitted through the mask to the detectorpixels under those regions. The size, shape, and arrangement of thelight-transmitting and light-blocking regions may be changed or adjustedin a temporally precise manner, and in some variations, in synchronywith a light source (e.g., a light source of an interferometry system).The light source may be a high-coherence source, a low-coherence source,a pulsed source (e.g., with microsecond, nanosecond, picosecond,femtosecond, etc. pulse width), or a continuous wave source. Examples ofa light source may include a super luminescent diode (SLD), a lightemitting diode (LED), a Ti:Saph laser, a white light lamp, adiode-pumped solid-state (DPSS) laser, a laser diode (LD), a lightemitting diode (LED), a super luminescent light emitting diode (sLED), atitanium sapphire laser, and/or a micro light emitting diode (mLED),among other light sources. The wavelength(s) of light generated by alight source may vary between about 350 nm to about 1.5 um, and/or maybe UV light, visible light, and/or near-infrared and infrared light. Thelight source may generate monochromatic light comprisingsingle-wavelength light, or light having multiple wavelengths (e.g.,white light). In some variations, a light source can emit a broadoptical spectrum or emit a narrow optical spectrum that is then rapidlyswept (e.g., changed over time) to functionally mimic or create aneffective broad optical spectrum. The size, shape, and arrangement ofthe light-transmitting and light-blocking regions may be determined atleast in part based on the number of light data acquisition time pointsin an acquisition window (which may correspond to number ofpredetermined phase shifts of the reference light in a set), imagefeature size (e.g., speckle grain size), size of the imager light sensorand/or detector pixel array, and to the extent that the patterncomprises repeating light-transmitting and light-blocking regions, thespatial frequency of the pattern may depend on the combination of thenumber of acquisition time points and image feature size. FIGS. 2B and2C depict example variations of optical mask patterns (i.e., patterns ona substrate of a mask or mask substrate patterns).

FIG. 2B depicts one variation of a mask substrate pattern (220)comprising a plurality of light-transmitting regions (222) and aplurality of light-blocking regions (224) in the form of stripes withdifferent widths, where the proportion of the total mask substrate(e.g., mask substrate area and/or width) occupied by light-transmittingstripes is about 10%. This mask substrate pattern may be used with, forexample, an imaging system where image data is acquired at 10 timepoints in an acquisition window. In the context of low-coherenceinterferometry or UOT, this pattern (220) may be used for theacquisition of interference patterns or speckle images that correspondto 10 predetermined phase shifts of the reference light signal. Masksubstrate pattern (220) may be one in a set of 10 patterns where thelight-transmitting stripes are shifted laterally by the width of astripe. For the mask pattern (220), each light-transmitting stripe (222)of width S_(w) is separated by a distance of 9*S_(w), such that there isone light-transmitting stripe (222) for every nine light-blockingstripes (224) (i.e., a ratio of a width of a light-transmitting stripe(222) to a width of a light-blocking stripe (224) of 1:9, also referredto as a width ratio). The mask substrate pattern (220) may be specificto the type of measurement being performed. For example, if atime-series analysis of 10 images is desired, for example, a 1:9 maskmay be used to recorded 10 time-series images on to one frame of theimager sensor. In this example, each image may have 1/10 the amount ofdata (i.e., 90% speckle image data is blocked by the mask device), butthis may be compensated for by using a high-pixel-count imager sensor.

FIG. 2C depicts another variation of a mask substrate pattern (230)comprising a plurality of light-transmitting regions (232) and aplurality of light-blocking regions (234) in the form of stripes withthe same (or similar) width, where the proportion of the total masksubstrate (e.g., mask substrate area and/or width) occupied bylight-transmitting stripes is about 50%. For the mask pattern (230),each light-transmitting stripe (232) of width S_(w) is separated by adistance of S_(w), such that there is one light-transmitting stripe(232) for every light-blocking stripe (234) (i.e., a width ratio of awidth of a light-transmitting stripe to a width of a light-blockingstripe of 1:1). This pattern may be used with, for example, an imagingsystem where image data is acquired at two time points in an acquisitionwindow. In the context of low-coherence interferometry or UOT, thispattern (230) may be used for the acquisition of interference patternsor speckle images that correspond to 2 predetermined phase shifts of thereference light signal. Mask substrate pattern (230) may be one in a setof two patterns where the light-transmitting stripes are shiftedlaterally by the width of a stripe.

FIG. 2D depicts a series of four predetermined mask substrateconfigurations or mask substrate patterns (242, 244, 246, 248)comprising a plurality of light-transmitting regions (241) and aplurality of light-blocking regions (243) in the form of stripes, wherethe proportion of the total mask substrate (e.g., mask substrate areaand/or width) occupied by light-transmitting stripes is about 25%. Foreach of the predetermined mask patterns depicted in FIG. 2D, eachlight-transmitting stripe (241) of width S_(w) is separated by adistance of 3*S_(w), such that there is one light-transmitting stripe(241) for every light-blocking stripe (243) that has a width of 3*S_(w)or three light-blocking stripes having a width of S_(w) (i.e., a widthratio of a width of a light-transmitting stripe to a width of alight-blocking stripe of 1:3). This pattern may be used with, forexample, an imaging system where image data is acquired at four timepoints in an acquisition window. In the context of low-coherenceinterferometry or UOT, the first mask substrate pattern (242) may beused for the acquisition of a first interference pattern or speckleimage that corresponds to a first predetermined phase shift of thereference light signal, the second mask substrate pattern (244) may beused for the acquisition of a second interference pattern or speckleimage that corresponds to a second predetermined phase shift of thereference light signal, the third mask substrate pattern (246) may beused for the acquisition of a third interference pattern or speckleimage that corresponds to a third predetermined phase shift of thereference light signal, and the fourth mask substrate pattern (248) maybe used for the acquisition of a fourth interference pattern or speckleimage that corresponds to a fourth predetermined phase shift of thereference light signal. The widths of the light-transmitting andlight-blocking stripes of each of the mask substrate patterns may be thesame, but may be spatially shifted laterally by a multiple of the widthof a stripe S_(w) (e.g., S_(w), 2*S_(w), 3*S_(w)). The four masksubstrate patterns may be created using an array of electrically-tunableoptical structures. Alternatively, these four substrate patterns may bemimicked with a single substrate pattern having a width ratio oflight-transmitting to light-blocking stripes of 1:3, and shifting ormoving the single substrate pattern across the light sensor region ofthe imager in steps, with step intervals that are the same size as (orapproximately the same size as) the stripe width S_(w). In the contextof low-coherence interferometry or UOT, such patterns may be used forthe acquisition of interference patterns or speckle images thatcorrespond to four predetermined phase shifts of the reference lightsignal. For example, the mask substrate may be adjusted to a firstpattern before a first light pulse or data acquisition time point, andthen adjusted to a second pattern before a second light source or dataacquisition time point. FIG. 2E depicts the mask substrateconfigurations or patterns (242, 244, 246, 248) disposed over an imagesensor (250) as the image sensor acquires four interference patterns orspeckle images (for example, each interference pattern may arise fromcombining the sample light pattern (light that has interacted withtissue) with a reference beam (light that has not interacted withtissue) having different relative phase shifts). An image sensor maycomprise a plurality of detector pixels in an array, and the differentmask substrate configurations may expose certain detector pixels (e.g.,the detector pixel regions located under the light-transmitting portionsof the mask substrate configuration or pattern) to acquire image data.The image data acquired for each of the four mask substrateconfigurations may be combined in a manner similar to that depicted inFIG. 1B to form a composite image. FIG. 2F depicts the image sensor(250) and the regions or sets of detector pixels that are located underlight-transmitting regions of the mask substrate configurations orpatterns in FIG. 2D. As schematically represented in FIG. 2F, a firstset of detector pixels (252) comprising stripes of detector pixelslocated under the light-transmitting stripes/regions of the first masksubstrate pattern or configuration (242), a second set of detectorpixels (254) comprising stripes of detector pixels located under thelight-transmitting stripes/regions of the second mask substrate patternor configuration (244), a third set of detector pixels (256) comprisingstripes of detector pixels located under the light-transmittingstripes/regions of the third mask substrate pattern or configuration(246), and a fourth set of detector pixels (258) comprising stripes ofdetector pixels located under the light-transmitting stripes/regions ofthe fourth mask substrate pattern or configuration (248).

The proportion or percentage of light-transmitting regions of a maskpattern over the total area of the substrate may be determined by thenumber (X) of images to be acquired by the imaging system during anacquisition time window (e.g., less than or equal to the acquisitiontime for a frame of data of the imager sensor, less than a speckledecorrelation time interval, from about 5 μs to about 100 μs, about 10μs, about 20 μs, about 40 μs, about 50 μs, about 100 μs, from about 500μs to about 1 ms, about 800 μs, about 1 ms, etc.), and may be (100/X) %.For example, for X=2 (which may simulate a 2-bin lock-in camera), a maskpattern may have a 50% fill-factor (i.e., a mask pattern where about 50%the area of the substrate is occupied by one or more light-blockingregions), and for X=4 (which may simulate a 4-bin lock-in camera), amask pattern may have a 75% fill-factor (i.e., a mask pattern whereabout 75% the area of the substrate is occupied by one or morelight-blocking regions and 25% of the area of the substrate is occupiedby one or more light-transmitting regions). The width of a stripe (ordimension of any pattern feature) may be determined at least in part byan image feature size, such as the size of a speckle grain, and/or thenumber of images to be captured in the acquisition time window (e.g.,less than the acquisition time for a frame of data of the imager sensor,less than a speckle decorrelation time interval, from about 5 μs toabout 100 μs, about 10 μs, about 20 μs, about 40 μs, about 50 μs, about100 μs, from about 500 μs to about 1 ms, about 800 μs, about 1 ms,etc.). The number of light-blocking stripes may be determined bydividing the area corresponding to the desired fill-factor by adimension (e.g., width) of a speckle grain and/or detector pixel. Insome variations, the mask substrate may be subdivided into stripes orchecks of arbitrary dimensions, and a set of X mask patterns foracquiring X number of images during an acquisition time window may bedetermined by selecting a portion of the stripes or checks to belight-transmitting (e.g., in proportion to X) for each mask pattern,where each stripe or check is a light-transmitting region for only onemask pattern. While the mask patterns described above and depicted inFIGS. 2B and 2C comprise stripes with uniform width repeated withuniform spacing, it should be understood that the patterns may comprisestripes with non-uniform or variable widths separated by non-uniformspacing, as long as the proportion of light-transmitting regions of themask pattern corresponds with the number of images captured by theimaging system during an acquisition time window as described above. Instill other mask pattern variations, patterns may comprise an array ofchecks (i.e., similar to a checkerboard) where the light-transmittingregions and light-blocking regions may be interspersed throughout thearray. The density of light-transmitting regions for some mask patternsmay be increased in regions of the image where higher levels ofresolution may be desired (e.g., where high-contrast and/orhigh-variable image features are expected).

Some optical mask devices may comprise substrates that are configured tovary the pattern of light-transmitting and light-blocking regions byadjusting or tuning the optical characteristics of certain regions ofthe substrate, which can change the location of the light-transmittingand light-blocking regions relative to the imager sensor without movingthe mask device with respect to the imager sensor. For example, anoptical mask device may comprise an electronically-controlled masksubstrate where the optical properties of the substrate may be spatiallymodulated, for example, based on absorption, retroreflection,transmission or other optical properties. In this matter, a masksubstrate may be able to change between at least two or more maskpatterns. Alternatively or additionally, the pattern on the substratemay not change, but the locations of the light-transmitting andlight-blocking regions of the mask device relative to the imager sensormay be changed by moving the mask device and/or imager sensor (“dynamicsensor”). A “dynamic mask” may refer to a movable mask and/or to a maskwith dynamically adjustable or tunable optical properties. The range ofmotion may be predetermined and on the order of several detector pixels,for example, approximately the size (e.g., width) of a speckle grain,and/or an integer number of detector pixels. In some systems, the maskpattern may change in conjunction with relative motion between the maskdevice and the imager sensor during image acquisition.

One variation of a mask device comprising a substrate that is configuredto change mask patterns may comprise an array of optical structures withelectrically-tunable optical properties. The optical structures may betuned to have the optical properties for a particular or predeterminedmask patterns based on mask configuration data transmitted from theimaging system controller to the mask. The area of the array of opticalstructures may correspond with the area of the light-sensing region ofthe imager sensor (e.g., approximately the area of the detector pixelarea of the imager sensor). In some variations, the optical structuresmay be electrically controllable optical modulators such as quantum wellheterostructures (e.g., with graded or stepped barriers), and/or othersemiconductor heterostructures with electrically tunable opticalproperties and high bandwidths of control, e.g., at MHz rates, and/orhigh-speed liquid crystal based transmission modulators, and/or digitalmicro-mirror device (DMD), and/or other micro-electro-mechanical systems(MEMS) based tunable/controllable reflector systems, and/or multi-layerLCD systems. In variations where a mask substrate comprises an array oftunable optical structures, these optical structures may be tiled intoalternating rows or columns where even rows or columns are controlled bya first control signal and odd rows or columns are controlled by asecond control signal, where the first and second control signals may befrom the mask device electronic circuitry and may be derived fromcommand signals from the imaging system controller (e.g., maskconfiguration data). It should be understood that the control signal(s),such as mask configuration signals, may be routed to the array ofoptical structures in any appropriate fashion such that thepredetermined mask patterns are replicated on the substrate inaccordance with the timing parameters set by the imaging systemcontroller (e.g., predetermined mask patterns m₀, m₁, m₂, . . . , m_(X)for corresponding acquisition time points t₀, t₁, t₂, . . . , t_(X)which may, in the context of low-coherence interferometry or UOTcorrespond with a predetermined reference light signal phase shifts p₀,p₀, p₀, . . . , p_(X) and so forth).

In one variation, a system controller in communication with a maskdevice substrate comprising an array of optical structures withelectrically-tunable optical properties may comprise a plurality of maskconfiguration signal channels (e.g., ports, data bus, wires, fibers,etc.), where the number of mask configuration signal channels correspondwith the number of optical structures in the mask substrate. Forexample, if a mask substrate comprises 64 optical structures, the systemcontroller may comprise 64 mask configuration signal channels, where thesignal on each channel drives the optical properties of a single opticalstructure. One example of mask configuration signals that may be used tocontrol electrically-tunable optical structures of a mask substrate tohave certain mask patterns or configurations is schematically depictedin FIGS. 2G and 2H. FIG. 2G depicts two mask substrate configurations orpatterns (260, 262) for a mask substrate comprising an array of 144electrically-tunable optical structures. The system controller (264) maybe connected to the mask device and/or mask substrate via 144 maskconfiguration signal channels, where each channel is mapped to anoptical structure of the array. To attain the first mask substratepattern or configuration (260) on the mask substrate, the systemcontroller (264) may generate 144 mask configuration signals (266) thatare transmitted over the mask configuration signal channels to the masksubstrate, where a signal value of “1” may indicate a high level ofopacity (e.g., light-blocking) and a signal value of “0” may indicate alow level of opacity (e.g., light-transmitting). To attain the secondmask substrate pattern or configuration (262) on the mask substrate, thesystem controller (264) may generate 144 mask configuration signals(268) that are transmitted over the mask configuration signal channelsto the mask substrate, where an optical element that had a low level ofopacity (e.g., light-transmitting) in the first mask substrate patternor configuration now has a high level of opacity (e.g., light-blocking)in the second substrate mask pattern or configuration.

A variety of mask substrate patterns or configurations may be attainedby adjusting the mask configuration signals. FIG. 2H depicts a differentset of predetermined mask substrate patterns (260, 262) for a masksubstrate comprising an array of 144 electrically-tunable opticalstructures. The system controller (264) may be connected to the maskdevice and/or mask substrate via 144 mask configuration signal channels,as described above. To attain the third mask substrate pattern orconfiguration (270) on the mask substrate, the system controller (264)may generate 144 mask configuration signals (276) that are transmittedover the mask configuration signal channels to the mask substrate, andto attain the fourth mask substrate pattern or configuration (272) onthe mask substrate, the system controller (264) may generate 144 maskconfiguration signals (278) that are transmitted over the maskconfiguration signal channels to the mask substrate. In othervariations, there may be more than two mask patterns or configurations(e.g., 3, 4, 5, 6, etc.) for any arbitrary-sized array of opticalstructures, and such patterns or configurations may be encoded in themask configuration signals as described above.

Alternatively or additionally, the pattern on a mask device may bestatic (e.g., where optical characteristics of electrically-tunableoptical structures are maintained or kept the same, where the substratecomprises materials or coatings arranged in a predetermined pattern thatcannot be optically tuned), but the mask device may be mechanicallymoved (e.g., stepped) relative to the imager sensor to predeterminedpositions corresponding to predetermined acquisition time points (thatmay correspond with a predetermined set of reference light signal phaseshifts) in an acquisition time window (e.g., which may be less than orequal to the acquisition time for a frame of data of the imager sensor,less than a speckle decorrelation time interval, from about 5 μs toabout 100 μs, about 10 μs, about 20 μs, about 40 μs, about 50 μs, about100 μs, from about 500 μs to about 1 ms, about 800 μs, about 1 ms,etc.). In some variations, the pattern of light-transmitting andlight-blocking regions on the mask substrate may comprise a pattern oflight-transmitting and light-blocking coatings, inks, materialsdeposited on the substrate. For example, light-transmitting regions maycomprise any light-transmissive materials such as glass, acrylic, and/orquartz glass, and may optionally include anti-glare coatings.Light-blocking regions may comprise any light-absorbing orlight-reflecting materials such as paints, carbon nanotube coatings,and/or black coatings such as black foil or polymer (e.g., blackcoatings and/or coated black foils manufactured by ACKTAR LTD,Kiryat-Gat, Israel). By moving or stepping the mask device across theimager sensor, the light-transmitting and light-blocking regions on themask are disposed over different sets of detector pixels at eachacquisition time point. A mask device position sensor may providereal-time data as to the position of the mask device to the imagingsystem controller so that the motion of the mask device can be adjustedaccordingly. Alternatively or additionally, the imager sensor may bemechanically moved (e.g., stepped) relative to the mask device topredetermined positions corresponding to predetermined acquisition timepoints (that may correspond with a predetermined set of reference lightsignal phase shifts) in an acquisition time window (e.g., which may beless than or equal to the acquisition time for a frame of data of theimager sensor, less than a speckle decorrelation time interval, fromabout 5 μs to about 100 μs, about 10 μs, about 20 μs, about 40 μs, about50 μs, about 100 μs, from about 500 μs to about 1 ms, about 800 μs,about 1 ms, etc.). The mechanical displacements of the mask deviceand/or imager sensor may be from about 2 μm to about 10 μm, and may insome variations depend on the detector pixel size of the imager sensor.The substrate may comprise one or more actuators, which may or may notbe integrated with the attachment structure. Similarly, the imagersensor may be coupled to one or more actuators. In some variations, thesubstrate and/or imager sensor may be attached to a mount that iscoupled to the actuator, which moves the mount to predeterminedlocations. Examples of actuators for moving the mask device and/orimager sensor may include piezoelectric positioners or materials, and/orpiezo actuators such as PLOXX PICMA® chip actuators (miniaturemultilayer piezo actuators by Physik Instrumente, Sausalito, Calif.)having sub-nanometer resolution, mechanical resonances greater than orequal to about 600 kHz. Multiple piezo actuators may be arranged inseries for larger ranges of motion. Motion of the imager sensor and/ormask device may optionally be combined with electrically tuning theoptical characteristics of the mask substrate (i.e., adjusting thelocation, size, and/or shape of light-transmitting and light-blockingregions). The location of the input speckle may also be synchronizedwith electronically controlled mask opening or configuration change. Forexample, a light-blocking region of a mask substrate disposed over oneor more detector pixels may transition to a light-transmitting region ofthe mask substrate (either by mechanically moving the mask orelectronically changing the optical property of the portion of thesubstrate disposed over the one or more detector pixels) when a speckleimage has a desired alignment with the one or more detector pixels. Thatis, the light from a speckle image is blocked when the one or moredetector pixels and/or mask device are not aligned (e.g., centered) withrespect to speckles in the image, and the light from the speckle imageimpinges on (i.e., is transmitted through the mask device substrateonto) the one or more detector pixels when the desired alignment isattained. Alternatively or additionally, the optical mask configuration(e.g., relative position of the light-transmitting and light-blockingregions on the mask device relative to the detector pixels of theimager, mask substrate pattern, relative mask and imager sensorposition) may be synchronized with the pulsing or strobing of a lightsource. For example, a change in the mask substrate configuration may besynchronized with a light source pulse. This may expand the ability ofthe imaging system to further tune or adjust light that is incident onevery detector pixel of the imager sensor, and/or to tune or adjust thedetection timing of a speckle grain at a detector pixel.

In the context of imaging a speckle pattern emerging from a scatteringmedium, to perform UOT, low-coherence interferometry or any wavefrontmeasurement for phase conjugation, it may be desirable to move theimager sensor relative to the mask device (i.e., keeping the mask devicestationary), especially if an imager sensor was selected with a detectorpixel size that approximates the speckle size. An imager sensor withdetector pixels that are similar in size to the anticipated specklegrain size may help increase speckle efficiency. This may allow half ofall speckles within the field of view of the imager to be measured,leading to ˜N/2 speckles captured where N is the number of detectorpixels, whereas other approaches may achieve N/X speckles captured whereX is the number of speckle patterns or images to be acquired during anacquisition time window, and in some variations may be greater than orequal to 2 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.). Increasing the numberof speckles measured in wavefront measurements schemes such as UOT orlow-coherence interferometry because shot noise in the measurement canbe suppressed or reduced by averaging over many distinct speckles, andsimilarly increasing the number of speckles measured is important inwavefront measurement for digital phase conjugation or wavefrontmodification. Obtaining measurements that include an increased number ofspeckles across a speckle image may facilitate the generation of a phaseconjugated wavefront that more precisely approximates (e.g., by havingmore optical modes) the wavefront of the light detected by the detectorpixels. If the mask is moved instead of the imager sensor, a specklegrain may be blocked from impinging on the imager if it does not followor track a light-transmitting region of the mask. Alternatively, thespeckle size may be increased (e.g., doubled to be approximately twicethe size as the detector pixels) such that the speckle may be detectedby one or more detector pixels in a light-transmitting region of themask.

In some variations, an imager may comprise an array of detector pixelsthat may be activatable by groups (e.g., rows, columns, clusters of rowsor columns) so that predetermined groups of detector pixels areacquiring image data at corresponding acquisition time points. Forexample, the imager circuitry may be configured to apply controlvoltages to specific detector pixels or groups of detector pixels (e.g.,one or more rows and/or columns of detector pixels), which maytransiently enable or disable the ability of the detector pixel todetect photons. A bias voltage may be applied to photodiodes containedin each detector pixel such that the detector pixel does or does notgenerate a photo-current depending on the applied bias voltage. Theactivation of certain groups or sets of detector pixels (e.g., via oneor more bias voltages) may be controlled by the imaging systemcontroller, which may store predetermined detector pixel activationpatterns corresponding to each data acquisition time point in acontroller member, and transmit command signals to the imager toactivate the appropriate detector pixels.

The imaging system controller may be in communication with the opticalmask device, and the imager (including imager sensor). The controllermay also be in communication with one or more actuators (as applicable)that are coupled to the mask device and/or imager sensor. In the contextof a low-coherence interferometry or UOT system, the imaging systemcontroller may also be in communication with an interferometer (e.g.,sample light source), and/or an acoustic assembly configured to deliverultrasound into the tissue. Optionally, the imaging system controllermay be in communication with an acousto-optic modulator. For example,the controller may transmit one or more synchronization signals to theinterferometer, and/or acoustic assembly, as well as the optical maskdevice and imager in order to ensure that image data is acquired at timepoints that correspond with changes in the sample light and/orultrasound pulses that are emitted to the tissue. With a common sync ortrigger signal across the various subcomponents of the imaging system,the acquired data may be analyzed according to the parameters (e.g.,phase shift, frequency shift, light intensities, etc.) of the lightand/or ultrasound pulses emitted into the tissue. For example, theoptical mask device may comprise an input port that receivessynchronization and/or mask substrate configuration signals from thatcontroller and an output port that transmits detector pixel array data(e.g., light intensities) to the controller for analysis. Bysynchronizing across these subcomponents, the controller can decode andanalyze the data from each detector pixel based on the maskconfiguration, reference light phase value, and/or ultrasound frequencytag to extract speckle data for each acquisition time point.

In some variations, the controller may be configured to calibrate therelative positions of the optical mask device and the imager sensor. Onevariation of a calibration method or protocol may comprise illuminatingthe entire optical mask device substrate area and imager sensor area(e.g., full-field illumination), changing the configuration of theoptical mask device to each of the predetermined mask configurations(e.g., mechanically moving the imager sensor and/or mask device,adjusting the optical characteristics of various regions of the masksubstrate) while acquiring a frame of image data for each maskconfiguration, and identifying any detector pixel regions in theacquired image data frames that have been illuminated in two maskconfigurations. This may indicate areas of overlap betweenlight-transmitting regions in two mask configurations. The actuatorand/or electrical control signals to the substrate may be adjusted toeliminate these overlaps.

FIG. 3A depicts one variation of an imaging system (300) comprising animager (302), an optical mask device (304) disposed over the imagersensor (306) and a system controller (308) in communication with theimager and the optical mask device. In some variations, the imager (302)and the optical mask device (304) may be enclosed in a common housing asan imager assembly (301). A low-coherence interferometry imaging systemmay comprise an interferometer including a sample light source (e.g.,laser (310)), and an UOT imaging system may further comprise anoptoacoustic modulator (312) and an ultrasound generator (314). Thelight source (310) may be configured to emit light pulses into sampletissue (e.g., skin surface on the head near a brain region of interest).The light source may be a high-coherence source, a low-coherence source,a pulsed source (e.g., with microsecond, nanosecond, picosecond,femtosecond, etc. pulse width), or a continuous wave source. Examples ofa light source may include a super luminescent diode (SLD), a lightemitting diode (LED), a Ti:Saph laser, a white light lamp, adiode-pumped solid-state (DPSS) laser, a laser diode (LD), a lightemitting diode (LED), a super luminescent light emitting diode (sLED), atitanium sapphire laser, and/or a micro light emitting diode (mLED),among other light sources. The wavelength(s) of light generated by alight source may vary between about 350 nm to about 1.5 um, and/or maybe UV light, visible light, and/or near-infrared and infrared light. Thelight source may generate monochromatic light comprisingsingle-wavelength light, or light having multiple wavelengths (e.g.,white light). In some variations, a light source can emit a broadoptical spectrum or emit a narrow optical spectrum that is then rapidlyswept (e.g., changed over time) to functionally mimic or create aneffective broad optical spectrum. The ultrasound generator (314) may beconfigured to emit ultrasound pulses and/or waves into the sampletissue, in synchrony with the light source, as coordinated by the systemcontroller. The system (300) may also comprise one or more actuators(316), which may be piezo actuators as described previously, coupled tothe imager sensor (306) and configured to move the sensor with respectto the mask device. The optical mask device (304) may comprise a maskposition sensor (305), and the imager sensor may be coupled to aposition sensor (307). As described previously, the mask device may becoupled to actuators configured to move the mask device relate to theimager sensor. In some variations, the mask device and/or the imagersensor may be moved and held at the predetermined position before a dataacquisition time point, which may help reduce or prevent blurring due tothe moving sensor and/or mask device. For example, the light source(310) may be synchronized with the ultrasound at predetermined dataacquisition time points that occur after motion of the sensor and/ormask have ceased.

FIG. 3B depicts an imaging system similar to the system of FIG. 3A,further comprising a shutter (e.g., motorized shutter, solenoid shutter,rotor drive shutter, stepper motor shutter, electronic shutter,acousto-optical modulator, electro-optic modulator, electricallycontrollable retroreflector, liquid crystal based modulator,polarization based modulator, etc.), chopper or other light blockingcomponent (318). Closing the shutter or chopper (318) during maskpattern reconfiguration and/or mask device motion and/or detector sensormotion may help to reduce image blurring. The system controller (308)may receive image data acquired by the imager sensor and timing dataassociated with the image data (e.g., a time stamp representing theabsolute time of image data acquisition, timing data representingrelative time of image data acquisition relative to other imaging systemcomponents). The system controller (308) may also coordinate the timingof the light source (310) pulses, ultrasound (314) pulses, maskconfiguration (e.g., pattern and/or position relative to the sensor),imager sensor position relative to the mask, and/or sensor acquisitiontiming to help alleviate or reduce blur artifacts and/or phase drifts.For example, the controller may coordinate the timing of the motion ofthe mask device and/or imager sensor so that their relative motion isnot driven at a resonant frequency. Optionally, some imaging systems maycomprise one or more vibration isolation mounts or pads coupled to anycomponents in the optical path to help reduce unwanted vibrations and/orpath length changes. This may help to reduce or eliminate any phasedrift that may occur due to relative motion of mask and sensor, sincephase drifts may result in unwanted blurring or mixing of specklepatterns between adjacent detector pixel columns on the imager sensor.In some variations, the system controller may phase-lock the sensor/maskmotion to the emission of sample light pulses from the light source(e.g., any of the light sources described above), and in the case ofUOT, ultrasound pulse emission. In addition, since the ultrasound wavesor pulses are slower than light waves, the system controller may triggerthe ultrasound source based on a trigger signal that occurs earlier thanthe light source trigger signal.

In some variations, an optical mask device may be used to create alock-in camera effect using two or more imager sensors rather than oneimager sensor. In this variation, a set of imager sensors arranged suchthat each of the detector pixels of one sensor is aligned with thecorresponding detector pixels of the other sensors (i.e., arranged in anOLIC-like system that comprises a plurality of separate imagers that areoptically aligned with each other, such that any given pixel(s) on theimagers have a known one-to-one correspondence with each other). Onevariation of such an imaging system is schematically depicted in FIG.4A. The imaging system (400) may comprise a first imager C1 having afirst imager sensor (402), a second imager C2 having a second imagersensor (404), a beam splitter (406) that directs light (e.g., from atissue sample) to both the first and second imagers C1 and C2, a firstoptical mask device (403) disposed in the optical path between thesplitter (406) and the first imager C1, and a second optical mask device(405) disposed in the optical path between the splitter (406) and thesecond imager C2. The first and second optical mask devices may have twomask configurations, the first light-blocking configuration comprising amask pattern where the entire area of the substrate over thelight-detecting region of the imager is light-blocking and the secondlight-transmitting configuration comprising a mask pattern where theentire area of the substrate over the light-detecting region of theimager is light-transmitting. In some variations, the first and secondoptical mask devices may comprise a shutter, which may include opticalchoppers, electronic shutters, optical modulators, liquid-crystalshutters, retroreflectors, or any other means of transiently blockinglight clocked with an external control signal. The timing between alight source (i.e., that emits a sample light pulse to tissue) and theoptical mask devices (403, 405) may allow the two imagers C1 and C2 tocapture time-dependent changes of the speckle pattern with arbitrarycontrol limited only by the speed of the optical mask devices (403,405). The two imager sensors (402, 404) may be aligned pixel-by-pixel soas to measure the same input speckle pattern in an OLIC-like scheme.Then, through the use of the two timed optical mask devices (whichtiming may be coordinated by the image system controller in accordancewith, for example, with the timing diagram of FIG. 4B), a first image iscaptured at time-point t₁ on the first sensor and then a second image iscaptured subsequently at a second time-point t₂ on the second sensor. Asshown in FIG. 4B, the first optical mask device (403, S1) is in thelight-transmitting configuration prior to the first light source pulseat time-point t₁, and the second optical mask device (405, S2) is in thelight-blocking configuration at time-point t₁. Although in this examplethe first and second imagers are continuously activated, only the firstimager (402) acquires any image data in this configuration because onlythe first optical mask device (403, S1) is in the light-transmittingconfiguration. After the first light source pulse, the first opticalmask device (403, S1) is transitioned to the light-blockingconfiguration and the second optical mask device (405, S2) istransitioned to the light-transmitting configuration. At time-point t₂,the second optical mask device (405, S2) is in the light-transmittingconfiguration while the first optical mask device (403, S1) is in thelight-blocking configuration, allowing the second imager (405) toacquire image data. FIG. 4A depicts the configuration at time-point t₁,where the first optical mask device (403) is in the light-transmittingconfiguration (e.g., shutter is open) and the second optical mask device(405) is in the light-blocking configuration (e.g., shutter is closed).In some variations, a first light source pulse may be used to create afirst interference or speckle pattern detected by the first imager atthe first time point, and a second light source pulse may be used tocreate a second interference or speckle pattern detected by the secondimager at the second time point. This is in contrast with other systems(e.g., an OLIC system) that uses a single light source pulse to generatean interference or speckle pattern that is measured by both imagers. Forexample, in a system comprising a laser light source, two short laserpulses each having a pulse width on the order of a few nanoseconds maybe used to generate interference patterns, rather than a single longlaser pulse having a width on the order of microseconds.

Methods

An imaging system comprising an imager with a conventional imager sensor(i.e., each detector pixel having a single electronic data bin storing asingle intensity value) and an optical mask device disposed over theimager sensor may be used in a variety of imaging contexts withdifferent imaging modalities. In some variations, the imaging systemsdescribed herein may be used in non-invasive optical brain imaging. Oneexample of non-invasive brain imaging comprises the detection ofballistic and/or quasi-ballistic photons using a low-coherenceinterferometry imaging system where the reference light is rapidlystepped through a predetermined set of phase shifts (e.g., X phaseshifts) that gives rise to a corresponding set of interference orspeckle light patterns (i.e., X interference light patterns). Detectionof ballistic photons (e.g., photons that have a path length that matchthe reference path length) and quasi-ballistic photons (e.g., photonsthat have a path length that approximates the reference path lengthwithin the coherence length of the light source) may help to generateimages of deep tissue structures and functional activities at higherresolution as compared to traditional diffuse optical tomographymethods. The set of phase shifts to the reference light may be appliedin a time frame shorter than a speckle decorrelation time interval(e.g., about 1 ms or less, 100 μs or less), generating X interference orspeckle patterns within that short time frame. An imaging systemcomprising an optical mask device with X patterns or configurations oflight-transmitting and light-blocking regions (such as any describedabove), may partition the detector pixel array of the imager sensor intoX sets of detector pixels, where each set of the X sets of detectorpixels is allocated for the acquisition of one of the X interferencepatterns. This may simulate the function of a X-bin lock-in camera. Byacquiring image data for the X interference patterns within the speckledecorrelation time interval, background light signals can be subtractedfrom the overall intensity calculation, leaving an intensity value ornumber of ballistic and/or quasi-ballistic photons that have beenemitted from the brain matter of interest. The intensity value ofballistic and/or quasi-ballistic photons may represent a physiologicalparameter of interest, for example, blood perfusion or flow rate to thebrain matter of interest. Additional details regarding the detection ofquasi-ballistic and/or ballistic photons using a low-coherenceinterferometry imaging system may be found in U.S. Non-Provisionalpatent application Ser. No. 15/853,538, filed Dec. 22, 2017 and U.S.patent application Ser. No. 15/853,209, filed Dec. 22, 2017, each ofwhich is hereby incorporated by reference in its entirety.

FIG. 5A depicts one variation of a method for non-invasive opticaldetection of neural activity. Method (500) may comprise adjusting (502)an optical mask device that is disposed over a light-sensing region ofan imager to have a first pattern of light-blocking regions andlight-transmitting regions, acquiring (504) a first set of lightinterference pattern data from brain matter at a first time point usinga first set of detector pixels in the light-sensing region of theimager, adjusting (506) the optical mask device to have a second patternof light-blocking region and light-transmitting regions, acquiring (508)a second set of light interference data from brain matter at a secondtime point using a second set of detector pixels in the light-sensingregion of the imager, and calculating (510) a light intensity value(e.g., a cumulative light intensity value) that represents neuralactivity in the brain matter by combining (e.g., by averaging, and/orcalculating a quadrature quantity, and/or taking a difference betweentwo intensity values, and/or taking an absolute value of a differencebetween intensity values, normalizing intensity values, etc.) intensityvalues of the first and second sets of detector pixels. For example, inthe context of acquiring speckle image data in an interferometry system(e.g., low-coherence interferometry for the detection of quasi-ballisticand/or ballistic photons, UOT, OCT, etc.), combining light intensitydata from the first and second sets of detector pixels may comprisecalculating the absolute difference of the intensity value of a firstdetector pixel in the first set with the intensity value of a seconddetector pixel in the second set that corresponds to the same speckle inthe speckle image (diff₀), calculating this absolute difference ofintensity values over all such corresponding pixel pairs between thefirst and second sets of detector pixels (i.e., calculating diff₀,diff₁, diff₂, . . . , diff_(Y), where Y is the number of pixels in eachset of detector pixels) and then averaging the these values to derive acumulative intensity value (i.e., cumulative intensity value is

$ {\frac{1}{Y}{\sum\limits_{i = 0}^{Y}{diff}_{i}}} ).$The difference in intensity values recorded by a first detector pixeland a corresponding second detector pixel may represent the intensitychanges of a single speckle over two time points, where the intensitychanges in that speckle may be due to shifting phases in a referencelight signal and/or light source, and/or changes in neural activity. Forexample, the first and second mask patterns (e.g., first and secondsubstrate configurations) may be used to acquire light interference datafrom first and second phase shifts of the reference light signal. In avariation where four sets of light interference pattern data (e.g.,speckle image data) are acquired over four sets of detector pixels usingfour mask substrate patterns or configurations, combining intensityvalues of four sets of detector pixels may comprise calculating aquadrature quantity of the intensity values of four individual detectorpixels, where each detector pixel is measuring the intensity of the samespeckle (i.e., recording the intensity changes of the speckle over fourtime points). Alternatively or additionally, intensity values of thedifferent sets of detector pixels may be combined by taking a differencebetween intensity values, and/or taking an absolute value of adifference between intensity values, normalizing intensity values, etc.of two or more detector pixels in two different sets. The combination ofintensity values over multiple sets of detector pixels that representchanges in light intensity of an interference pattern over time may beused to derive a cumulative light intensity value or quantity thatrepresents neural activity and/or physiological activity over time(e.g., deoxygenated and/or oxygenated hemoglobin concentration, waterconcentration, and/or electrical and/or synaptic activity, etc.) at thebrain matter of interest. The steps (502-508) of the method (500) may beperformed within a speckle decorrelation time interval, and mayoptionally be repeated for third and fourth mask patterns (e.g., thirdand fourth substrate configurations) to acquire light interference datafrom third and fourth phase shifts of the reference light signal (whereall four phase shifts occur within the speckle decorrelation timeinterval). Method (500) may optionally comprise calculating a cumulativeintensity value over four intensity values may comprise methods andprinciples of quadrature detection, and similarly averaged over all thepixels in each set of detector pixels. For example, the sample light maybe stepped through there may be two phase shifts, where the first phasemay be 0 and the second phase may be π, or may be stepped through fourphase shifts, where the phase values may be 0, π/2, π, and 3π/2.

FIG. 5B depicts another variation of a method for non-invasive opticaldetection of neural activity using an imaging system with an opticalmask device disposed over a detector pixel array of a conventionalimager. Method (520) may comprise adjusting (522) positions oflight-blocking and light transmitting region of an optical mask deviceat a predetermined number (X) of time points to a plurality ofpredetermined positions that correspond with (or in synchrony with) apredetermined number of phases of a reference light signal, acquiring(524) light interference data for each of the plurality of predeterminedpositions using the detector pixel array, and calculating (526) aplurality (X) of light intensity values corresponding to the number (X)of phases of the reference light signal, wherein changes in theplurality of light intensity values over time represent neural activity.Calculating a plurality of light intensity values may comprise averaging(or otherwise combining) imager detector pixel values for each of thepredetermined number of time points.

For ultrasound modulated optical tomography (UOT) and low-coherenceinterferometry for the detection of quasi-ballistic and/or ballisticphotons, through heterodyne parallel speckle detection,ultrasound-tagged light may be differentiated from the reference lightsignal (i.e., light from the light source that is not emitted to thebrain tissue) and untagged light in a speckle image. This may beattained by isolating the interference term that contains a contributionfrom the tagged light while subtracting away other interference terms,which can be attained, for example, by phase-shifting holography. Aconventional imager and an optical mask device (such as any of the maskdevices described herein) can attain this acquiring by subtracting theintensity data acquired using a second mask (intensitydata2) from theintensity data acquiring using a first mask (intensitydata1) in the casewhere there are two phase shifts, or by(intensitydata4−intensitydata2)²+(intensitydata3−intensitydata1)², i.e.,quadrature implementation, in the case where there are four phaseshifts. In one implementation, each interference pattern is presented tothe sensor at a different time and with a different relative phase shiftbetween the reference beam (light that has not interacted with tissue)and the sample light pattern (light that has interacted with tissue).These phase shifts and interference patterns are acquired within thespeckle decorrelation time interval for a decorrelating tissuescattering medium. Alternatively, an oscillating heterodyne interferenceterm that represents a combination of the different frequencies of thedifferent light signals that combine to form an interference pattern(e.g., a sum or difference of frequencies f₁ and f₂, where f₁ is afrequency of a first light interference pattern and f₂ is a frequency ofa second light interference pattern) can be detected by sampling at 2×or 4× the beat frequency (e.g., 2×, 3×, 5×, 6×, etc. the beat frequency)using a conventional imager and the mask configuration described above,and performing similar calculations.

In a non-limiting UOT example, a 1 MHz ultrasound pulse in the samplemay be used to shift the base optical frequency of light by 1 MHz. Thereis also a reference (with per-pixel power denoted P_(ref)) light sourcethat is shifted by 2 MHz, and untagged light at the base frequency. Thetotal measurement takes 1 μs. In the first half of the process (e.g., afirst 500 ns), the light-transmitting regions of the mask pattern mayallow a speckle pattern to fall on all the “odd” detector pixel columnsof the imager sensor while the “even” detector pixel columns are locatedunder light-blocking regions of the pattern. At the 500 ns time point,the sensor may be shifted by one detector pixel column width, to allowthe speckle pattern to fall on the “even” detector pixel columns of thesensor. After another 500 ns the measurement is completed, andalternating columns of interference image data have been obtained.

In the formulas below, unknown₁, unknown₂, unknown₃ indicate the unknownrelative wavefront phases of the light arriving at the detector pixeldue to the scattering medium (e.g., brain tissue). These are differentfor each detector pixel due to the randomness of the speckleinterference (as well as rapidly changing due to decorrelation), as arethe intensities of the P_(untagged) and P_(tagged). Instantaneousintensity on particular pixel, P_(1,1)=P _(ref) +P _(untagged) +P _(tagged)+2*sqrt(P _(reference) *P_(tagged))*cos(2π*1 MHz*time+unknown₁)2*sqrt(P _(reference) *P _(untagged))*cos(2π*2 MHz*time+unknown₂)2*sqrt(P _(untagged) *P _(tagged))*cos(2π*1 MHz*time+unknown₃)

The measured charge on detector pixel P_(1,1) may be proportional to theintegral of the above equation in the time between 0 and 500 ns themeasured intensity of the detector pixel is, given that the product ofthe untagged and reference light integrates to close to zero,500 ns*[P _(ref) +P _(untagged) +P _(tagged)]+sqrt(P _(reference) *P_(tagged))*[−2 sin(unknown₁)]/(2π*1 MHz)+sqrt(P _(untagged) *P_(tagged))*[−2 sin(unknown₃)]/(2π*1 MHz)

The second part of the image may be captured during the time from 500 nsto 1 μs which is assigned to the neighboring column for a specificpixel, P_(1,2). Measured intensity on a particular pixel following theintegration is P_(1,2)=500 ns*[P _(ref) +P _(untagged) +P _(tagged)]+sqrt(P _(reference) *P_(tagged))*[2 sin(unknown₁)]/(2π*1 MHz)+sqrt(P _(untagged) *P_(tagged))*[2 sin(unknown₃)]/(2π*1 MHz)

By taking the absolute difference |P_(1,1)-P_(1,2)|, the DC backgroundterms P_(ref)+P_(untagged)+P_(tagged) may be removed:|4*sqrt(P _(reference) *P _(tagged))*[sin(unknown₁)]+4*sqrt(P_(untagged) *P _(tagged))*[sin(unknown₃)]|/(2π*1 MHz)

By summing or averaging these absolute differences, of neighboringcolumn values at each row, across the entire imager sensor and assumingthat P_(reference) and P_(untagged) are relatively static over time, theresulting single value may be linear with P_(tagged), and may representa physiological optical parameter (e.g., level of deoxygenated and/oroxygenated hemoglobin concentration of relative abundance, level ofwater concentration or relative water concentration).

Although particular embodiments of the present inventions have beenshown and described, it will be understood that it is not intended tolimit the present inventions to the disclosed embodiments, and it willbe obvious to those skilled in the art that various changes andmodifications may be made without departing from the spirit and scope ofthe present inventions. Thus, the present inventions are intended tocover alternatives, modifications, and equivalents, which may beincluded within the spirit and scope of the present inventions asdefined by the claims.

The invention claimed is:
 1. A system for non-invasive optical detectionof neural activity comprising: an imager having a light-sensing region;an optical mask device configured to be disposed over the light-sensingregion of an imager; a beam splitter configured to split a light beaminto a sample light signal and a reference light signal, and direct thesample light signal to a tissue sample of an anatomical structure andthe reference light signal along a light path that does not interactwith the tissue sample of the anatomical structure, the reference lightsignal configured to cycle through a plurality of phases; and acontroller configured to adjust the optical mask device to have a firstpattern of light-blocking regions and light-transmitting regions, directthe imager to acquire, while the optical mask has the first pattern oflight-blocking regions and light-transmitting regions and while thereference light signal has a first phase included in the plurality ofphases, a first set of light interference pattern data from the tissuesample at a first time point using a first set of detector pixels in thelight-sensing region of the imager, the first light interference patterndata comprising a combination of the reference light signal having thefirst phase and the sample light signal after the sample light signalinteracts with the tissue sample, adjust the optical mask device to havea second pattern of light-blocking regions and light-transmittingregions, direct the imager to acquire, while the optical mask has thesecond pattern of light-blocking regions and light-transmitting regionsand while the reference light signal has a second phase included in theplurality of phases, a second set of light interference data from thetissue sample at a second time point using a second set of detectorpixels in the light-sensing region of the imager, the second lightinterference pattern data comprising a combination of the referencelight signal having the second phase and the sample light signal afterthe sample light signal interacts with the tissue sample, and calculatea first light intensity value by combining intensity values of eachdetector pixel in the first set of detector pixels and calculating asecond light intensity value by combining intensity values of eachdetector pixel in the second set of detector pixels; wherein acombination of the first light intensity value and the second lightintensity value represents the neural activity.
 2. The system of claim1, wherein the detector pixels in the second set are different from thedetector pixels in the first set.
 3. The system of claim 1, wherein thefirst phase is 0 and the second phase is π.
 4. The system of claim 1,wherein the controller is further configured to determine aphysiological optical parameter of the tissue sample based on the firstand second light intensity values.
 5. The system of 1, wherein thecontroller is further configured to: adjust the optical mask to have athird pattern of light-blocking regions and light-transmitting regions;direct the imager to acquire, while the optical mask has the thirdpattern of light-blocking regions and light-transmitting regions andwhile the reference light signal has a third phase included in theplurality of phases, a third set of light interference data from thetissue sample at a third time point using a third set of detector pixelsin the light-sensing region of the imager, wherein the third lightinterference pattern data comprises a combination of the reference lightsignal having the third phase and the sample light signal after thesample light signal interacts with the tissue sample; adjust the opticalmask to have a fourth pattern of light-blocking regions andlight-transmitting regions; direct the imager to acquire, while theoptical mask has the fourth pattern of light-blocking regions andlight-transmitting regions and while the reference light signal has afourth phase included in the plurality of phases, a fourth set of lightinterference data from the tissue sample at a fourth time point using afourth set of detector pixels in the light-sensing region of the imager,wherein the fourth light interference pattern data comprises acombination of the reference light signal having the fourth phase andthe sample light signal after the sample light signal interacts with thetissue sample; and calculate a third light intensity value by combiningintensity values of each detector pixel in the third set of detectorpixels and calculating a fourth light intensity value by combiningintensity values of each detector pixel in the fourth set of detectorpixels.
 6. The system of claim 5, wherein: the first phase is 0, thesecond phase is π/2, the third phase is π, and the fourth phase is 3π/2;and the controller is further configured to determine a physiologicaloptical parameter of the tissue sample based on the first, second,third, and fourth light intensity values.
 7. A system for non-invasiveoptical measurement of neural activity comprising: an optical splitterconfigured to split a light beam into a sample light signal and areference light signal, and direct the sample light signal to a tissuesample of an anatomical structure and the reference light signal along alight path that does not interact with the tissue sample of theanatomical structure, the reference light signal configured to cyclethrough a predetermined number (N) of phases; and a controllerconfigured to adjust positions of light-blocking and light-transmittingregions of an optical mask at a predetermined number (X) of time pointsto a plurality of predetermined positions that correspond with thepredetermined number (N) of phases of the reference light signal,wherein the optical mask is disposed over a detector pixel array of animager, direct the imager to acquire light interference data for each ofthe plurality of predetermined positions using the detector pixel array,and calculate a plurality (X) of light intensity values corresponding tothe predetermined number (N) of phases of the reference light signal byaveraging imager detector pixel values for each of the predeterminednumber (X) of time points, wherein changes in the plurality of lightintensity values over time represent neural activity.